Genetics - Theses
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ItemComparative analysis of dimorphic growth in the pathogenic fungus Penicillium marneffei( 2013)Fungal infection is a major cause of mortality in immunocompromised individuals and an escalating health threat in the 21st century. With very little known about the mechanisms behind its virulence, Penicillium marneffei is a dimorphic opportunistic fungal pathogen of humans. At 25°C P. marneffei grows as multicellular nonpathogenic hyphae that through differentiation produces asexual conidia, the infectious agent. Infection begins with the inhalation of conidia, followed by a dimorphic switch of these conidia to pathogenic yeast cells upon entering the 37°C environment of the host. In the host P. marneffei resides within immune phagocytic cells, where it then grows as a fission yeast. The objective of this study was to identify differences between P. marneffei hyphal and yeast cells. For this purpose, firstly extensive microarray-based expression profiling data was analysed, identifying a variety of differentially expressed genes that were organized into clusters based on function and spatiotemporal expression patterns. One key activity highlighted in the data related to the acquisition of the essential trace metal iron. Genes involved in high-affinity iron assimilation systems, their regulation and the production of key iron acquisition secondary metabolites (siderophores) were characterised in both hyphal and yeast cells. It was found that compared to hyphal cells, yeast cells rely more heavily on iron acquisition through high-affinity reductive iron assimilation. Also, at least under rich iron conditions there is a yeast cell-specific upregulation of genes involved in the biosynthesis of extracellular siderophores, via the de-repression of transcriptional regulation by SreA. Secondly, metabolite profiling and ‘footprint’ analyses of hyphal and yeast cells were performed. This snapshot of P. marneffei metabolism revealed the metabolite differences between the two cell types and pointed to the utilisation of specific pathways in each growth form. Further, 13C-labeled glucose experiments revealed an increase in specific carbon metabolic pathways in yeast cells, particularly the TCA cycle and the pentose phosphate cycle, indicative of responses to stressful environments. By combining data derived from multiple molecular approaches, key metabolic networks were reconstructed and results highlight that P. marneffei hyphal and yeast cells have definitively different developmental and nutritional profiles, reminiscent of their mode of reproduction and likely adaptations to the environmental niche they inhabit.